Date of Award

2019

Degree Type

Dissertation

Degree Name

Doctor of Philosophy in Pharmaceutical Sciences

Department

Biomedical and Pharmaceutical Sciences

First Advisor

Xinyuan Chen

Abstract

Oral drug delivery has been the major route of drug delivery due to the ease of drug administration and patient compliance. Transdermal drug delivery is highly attractive for alternative drug delivery and yet faces significant challenges, largely due to the barrier function of the Stratum Corneum (SC) layer of the skin. Different chemical and physical methods have been explored to disrupt the SC layer to facilitate transdermal drug delivery. However, those methods only received limited successes due to the low efficiency in SC disruption or the potential safety risks.

Ablative fractional laser (AFL) emerged in the last 2 decades as a novel technology for safe and efficient ablation of SC layer to facilitate transdermal drug delivery. AFL was fabricated based on the concept of fractional photothermolysis for improved skin resurfacing in cosmetic field. This technology emits tiny laser beams on skin surface to instantly increase skin temperature to over 100°C and cause tissue evaporation. Because of this, tiny microchannels (MCs) are generated on skin surface to allow drugs to migrate into the skin with high efficiency. At the same time, the MCs can achieve quick and complete skin recovery in 2-3 days considering each of these MCs is surrounded by normal healthy skin with a good repairing capacity. AFL adequately addresses the dilemma about the safety and efficiency of SC ablation to facilitate transdermal drug delivery. The current dissertation focuses on developing novel delivery platforms for use in conjunction with AFL for extended drug release (Manuscript I and III) and transcutaneous vaccination (Manuscript II).

In manuscript I, we coated ‘bulk’ amount of drug powder into reservoir patches and then topically applied onto AFL-treated skin to elicit multi-day sustained drug release. We found tapped coating could elicit 3-day sustained drug release, while compression coating could elicit 6-day sustained drug release. Drugs in gram scales can be potentially delivered via AFL-assisted reservoir patch delivery with compression coating. We further found such a delivery platform is suitable for the delivery of both small chemicals and macromolecules.

In manuscript II, we coated vaccine powder on full-surface adhesive patches followed by topical application onto AFL-treated skin for transcutaneous vaccination. Beside delivery of vaccines alone, we found a clinical monophosphoryl lipid a (MPL) adjuvant could be encapsulated into poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) for delivery together with vaccines via the same delivery platform. AFL-assisted full-surface powder vaccine/MPL delivery induced much stronger vaccine-specific immune responses than vaccine delivery alone in both newborn and adult mice.

In manuscript III, we embedded drugs into hydrogels for delivery via AFL-generated skin MCs. We found poly (vinyl alcohol) (PVA) hydrogel but not poly (2- hydroxyethyl methacrylate) (pHEMA) hydrogel could serve as an efficient delivery platform to deliver drugs via AFL generated skin MCs. AFL-assisted PVA hydrogel-based zidovudine delivery was found to elicit almost 100% delivery efficiency and at the same time extend drug release to ~15 hours, while oral delivery only induced sustained release for up to 3 hours.

AFL-assisted high-dose 6-day sustained powder drug delivery is promising to reduce dosing frequency and improve patient adherence in treatment of long-term chronic diseases. AFL-assisted hydrogel-based drug delivery provides another delivery platform for extended delivery of hydrophilic drugs. AFL-assisted full-surface vaccine/MPL delivery represents an innovative transcutaneous vaccination technology for needle-free delivery and adjuvantation of vaccine immunization. The needle-free AFL-based drug/vaccine delivery platform warrants further investigation for human use.

Available for download on Monday, April 19, 2021

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